Bottom Line:
Bacterial enzymes have long been considered solely accountable for the degradation of the dentin matrix during the carious process.Furthermore, the potential release of bioactive peptides by the enzymatic cleavage of dentin matrix proteins by MMPs during the carious process is discussed.These peptides, once identified, may constitute promising therapeutical tools for tooth and bone regeneration.

ABSTRACTBacterial enzymes have long been considered solely accountable for the degradation of the dentin matrix during the carious process. However, the emerging literature suggests that host-derived enzymes, and in particular the matrix metalloproteinases (MMPs) contained in dentin and saliva can play a major role in this process by their ability to degrade the dentin matrix from within. These findings are important since they open new therapeutic options for caries prevention and treatment. The possibility of using MMP inhibitors to interfere with dentin caries progression is discussed. Furthermore, the potential release of bioactive peptides by the enzymatic cleavage of dentin matrix proteins by MMPs during the carious process is discussed. These peptides, once identified, may constitute promising therapeutical tools for tooth and bone regeneration.

Figure 1: Schematic representation of MMP activity during the dentin carious process. Cariogenic bacteria present in the caries cavity release acids such as lactic acid that reduce the local pH. The resulting acidic environment demineralizes the dentin matrix and induces the activation of host MMPs derived from dentin or saliva (which bathes the caries cavity). Once the local pH is neutralized by salivary buffer systems, activated MMPs degrade the demineralized dentin matrix.

Mentions:
Host MMPs derived from dentin or saliva have been shown to be able to degrade the dentin matrix which has been previously demineralized by bacterial acids (Tjaderhane et al., 1999; Chaussain-Miller et al., 2006) (Figure. 1). Saliva contains several MMPs including collagenases and gelatinases derived from either the gingival crevicular fluid or the secretion of salivary glands, MMP-9 being the most abundant as it is derived from both sources (Van Strijp et al., 2003). Indeed, the incubation of demineralized dentin slabs with acid-pretreated saliva resulted in the degradation of the organic matrix (Van Strijp et al., 2003). As saliva bathes the carious lesions, it is not surprising that the active form of MMP-9 was systematically detected by zymography performed on dentin extracts from several carious teeth (Tjaderhane et al., 1998). Together these studies indicate that salivary MMPs may have a strong contribution to dentin matrix degradation during the caries process. Carious lesions were also found to contain both latent and active forms of MMP-3, MMP-2 and MMP-8 (Tjaderhane et al., 1998; Mazzoni et al., 2007; Sulkala et al., 2007; Boukpessi et al., 2008). Along this line, dentin protein extracts obtained from the different dentin layers of decayed teeth were shown to have their gelatinase activity gradually increased from healthy dentin extracts to soft infected dentin extracts (superficial soft carious lesion, inner soft carious lesion, affected dentin, sound dentin) (Charadram et al., 2012). These observations confirm that endogenous MMP-2 contained within the sound dentin is activated during the carious process (Figure. 2). It has also been suggested by immunohistochemical observations that the endogenous MMP-2 level may be increased through the induction of MMP-2 synthesis by the presence of caries (Toledano et al., 2010). This was supported by a study showing that MMP-2 and TIMP-2 gene expressions were significantly up-regulated in odontoblasts adjacent to the carious lesion (Charadram et al., 2012). Interestingly, several studies have reported that in the cancer context, MMP expression by tumor cells was up-regulated by an acidic extracellular pH (Kato et al., 2005; Rofstad et al., 2006). This can suggest that acidic pH during the carious process may both induce MMP expression by the odontoblasts and favor their activation, potentiating MMP proteolytic capacity. In addition, the expression of MT1-MMP, a potent activator of MMP-2 and MMP-20 (Palosaari et al., 2002), was also dramatically increased in these cells, enhancing dentin matrix degradation. In addition, MMP-2, MMP- 20 and cathepsin B were shown to be present in dentinal fluid, where they may contribute to peritubular dentin degradation especially in young patients who have large and numerous dentin tubules (Sulkala et al., 2002; Boushell et al., 2008; Tersariol et al., 2010). Importantly, a study performed in a rat caries model has shown that MMP inhibition by several synthetic inhibitors reduced dentin caries progression under fissures (Sulkala et al., 2001). This study not only confirms the role of host MMPs in the caries process but also raises the possibility of using MMP inhibitors for impairing dentin matrix degradation during the caries.

Figure 1: Schematic representation of MMP activity during the dentin carious process. Cariogenic bacteria present in the caries cavity release acids such as lactic acid that reduce the local pH. The resulting acidic environment demineralizes the dentin matrix and induces the activation of host MMPs derived from dentin or saliva (which bathes the caries cavity). Once the local pH is neutralized by salivary buffer systems, activated MMPs degrade the demineralized dentin matrix.

Mentions:
Host MMPs derived from dentin or saliva have been shown to be able to degrade the dentin matrix which has been previously demineralized by bacterial acids (Tjaderhane et al., 1999; Chaussain-Miller et al., 2006) (Figure. 1). Saliva contains several MMPs including collagenases and gelatinases derived from either the gingival crevicular fluid or the secretion of salivary glands, MMP-9 being the most abundant as it is derived from both sources (Van Strijp et al., 2003). Indeed, the incubation of demineralized dentin slabs with acid-pretreated saliva resulted in the degradation of the organic matrix (Van Strijp et al., 2003). As saliva bathes the carious lesions, it is not surprising that the active form of MMP-9 was systematically detected by zymography performed on dentin extracts from several carious teeth (Tjaderhane et al., 1998). Together these studies indicate that salivary MMPs may have a strong contribution to dentin matrix degradation during the caries process. Carious lesions were also found to contain both latent and active forms of MMP-3, MMP-2 and MMP-8 (Tjaderhane et al., 1998; Mazzoni et al., 2007; Sulkala et al., 2007; Boukpessi et al., 2008). Along this line, dentin protein extracts obtained from the different dentin layers of decayed teeth were shown to have their gelatinase activity gradually increased from healthy dentin extracts to soft infected dentin extracts (superficial soft carious lesion, inner soft carious lesion, affected dentin, sound dentin) (Charadram et al., 2012). These observations confirm that endogenous MMP-2 contained within the sound dentin is activated during the carious process (Figure. 2). It has also been suggested by immunohistochemical observations that the endogenous MMP-2 level may be increased through the induction of MMP-2 synthesis by the presence of caries (Toledano et al., 2010). This was supported by a study showing that MMP-2 and TIMP-2 gene expressions were significantly up-regulated in odontoblasts adjacent to the carious lesion (Charadram et al., 2012). Interestingly, several studies have reported that in the cancer context, MMP expression by tumor cells was up-regulated by an acidic extracellular pH (Kato et al., 2005; Rofstad et al., 2006). This can suggest that acidic pH during the carious process may both induce MMP expression by the odontoblasts and favor their activation, potentiating MMP proteolytic capacity. In addition, the expression of MT1-MMP, a potent activator of MMP-2 and MMP-20 (Palosaari et al., 2002), was also dramatically increased in these cells, enhancing dentin matrix degradation. In addition, MMP-2, MMP- 20 and cathepsin B were shown to be present in dentinal fluid, where they may contribute to peritubular dentin degradation especially in young patients who have large and numerous dentin tubules (Sulkala et al., 2002; Boushell et al., 2008; Tersariol et al., 2010). Importantly, a study performed in a rat caries model has shown that MMP inhibition by several synthetic inhibitors reduced dentin caries progression under fissures (Sulkala et al., 2001). This study not only confirms the role of host MMPs in the caries process but also raises the possibility of using MMP inhibitors for impairing dentin matrix degradation during the caries.

Bottom Line:
Bacterial enzymes have long been considered solely accountable for the degradation of the dentin matrix during the carious process.Furthermore, the potential release of bioactive peptides by the enzymatic cleavage of dentin matrix proteins by MMPs during the carious process is discussed.These peptides, once identified, may constitute promising therapeutical tools for tooth and bone regeneration.

ABSTRACTBacterial enzymes have long been considered solely accountable for the degradation of the dentin matrix during the carious process. However, the emerging literature suggests that host-derived enzymes, and in particular the matrix metalloproteinases (MMPs) contained in dentin and saliva can play a major role in this process by their ability to degrade the dentin matrix from within. These findings are important since they open new therapeutic options for caries prevention and treatment. The possibility of using MMP inhibitors to interfere with dentin caries progression is discussed. Furthermore, the potential release of bioactive peptides by the enzymatic cleavage of dentin matrix proteins by MMPs during the carious process is discussed. These peptides, once identified, may constitute promising therapeutical tools for tooth and bone regeneration.